ABSTRACT The response to a severe burn is characterized by persistent hypermetabolic and catabolic state that result in the massive loss of muscle tissue, even in the fed state. In patients with > 30% of total body surface area burned, protein breakdown persists for approximately one year after the burn wound is 95% healed. Endogenous catecholamines have been implicated as primary mediators of the hypermetabolic response to trauma or burn. Chronic elevation of plasma catecholamine levels results in the development of hyperdynamic circulation, increased basal energy expenditure, peripheral insulin resistance with hyperglycemia, increased peripheral lipolysis, depressed immune function, skeletal muscle protein catabolism and hypertrophic scarring. The hypermetabolic response to burns is also characterized by a profound tachycardia and increased cardiac work that are detrimental to the heart. The persistence of tachycardia and muscle catabolism significantly compromises rehabilitation and results in an excessive delay before resuming normal physical and functional activities. Recent studies from our institution have shown the negative impact of hyperglycemia and insulin resistance on survival, wound healing, and skeletal muscle catabolism. Insulin resistance can last for at least 3 years in severely burned patients, further delaying a patient's return to normal and reducing their quality of life. In the previous funding period, we demonstrated that administration of intensive insulin alone or in combination with propranolol improves outcomes for severely burned patients. However, the use of insulin was associated with high levels of hypoglycemia. Therefore, we now will utilize an anti-hyperglycemic therapy that does not have the risk of hypoglycemia. We have shown that acute administration of fenofibrate, a fibrate, reduces blood glucose levels in severely burned patients. We will now administer fenofibrate alone or in combination with propranolol to determine the clinical efficacy and underlying mechanisms of action on insulin resistance, wound healing, sepsis, and cardiac function. We hypothesize that reduction of blood glucose levels, along with blockade of catecholamines, will result in attenuation of the long-term post-burn catabolic and hypermetabolic responses, and that these responses will be ameliorated by the therapeutic use of fenofibrate alone or in combination with propranolol, administered for one year post burn. A total of 300 patients will be randomized to receive daily administration of Fenofibrate alone or in combination with propranolol. Comparison of the data from these patients to an equal number of placebo- or propranolol-treated patients will be accomplished using data from our already funded P50 burn center trial which will be completed by January 2015.